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The new england journal of medicine

Review Article

John A. Jarcho, M.D., Editor Lipid Management for the Prevention of Atherosclerotic Cardiovascular Disease

Erin D. Michos, M.D., M.H.S., John W. McEvoy, M.B., B.Ch., M.H.S., and Roger S. Blumenthal, M.D.​​

n 1961, the investigators involved in the Framingham Heart Study From the Ciccarone Center for the Pre- identified serum as one of the “factors of risk” for coronary heart vention of Cardiovascular Disease, Johns 1 Hopkins University School of Medicine, disease. Since then, numerous epidemiologic studies and randomized clinical Baltimore (E.D.M., R.S.B), and the Na- I tional Institute for Prevention and Cardio- trials have established that an elevated level of low-density (LDL) choles- terol is a major contributor to atherosclerotic cardiovascular disease.2,3 As a con- vascular Health, National University of Ireland, Galway (J.W.M.). Address reprint sequence, the management of serum cholesterol levels has become a central objec- requests to Dr. Michos at the Division of tive in the effort to prevent cardiovascular events. The currently used therapies Cardiology, Johns Hopkins School of with demonstrated efficacy (see Table S1 in the Supplementary Appendix, avail- Medicine, Blalock 524-B, 600 N. Wolfe St., Baltimore, MD 21287, or at ­edonnell@​ able with the full text of this article at NEJM.org) predominantly target the apolipo- jhmi­ .​ edu.­ protein B–associated reflected in levels of LDL cholesterol, non–high- N Engl J Med 2019;381:1557-67. density lipoprotein cholesterol (non-HDL cholesterol), and (Fig. 1). DOI: 10.1056/NEJMra1806939 The most recent guidelines for cholesterol management put forward by the Copyright © 2019 Massachusetts Medical Society. American College of Cardiology–American Heart Association (ACC–AHA) were published in 2018 (Fig. 2).4 In 2019, the ACC–AHA published guidelines for the primary prevention of cardiovascular disease, carrying forward recommendations for risk estimation and lipid management from the 2018 guidelines on cholesterol management.5 Informed by these new guidelines and other recent advances in treatment, this review is intended to summarize current methods of managing serum lipid levels for the prevention of atherosclerotic cardiovascular disease.

Lifestyle Management The foundation for managing serum cholesterol is the facilitation of a healthy lifestyle (which includes diet) across a person’s life span.5,6 Even persons whose genetic profile puts them at increased risk for coronary heart disease can reduce their risk by up to 50% through changes in lifestyle.7 Maintenance of a normal weight and blood sugar level, reduction in the intake of simple sugars and refined carbohydrates, and increases in physical activity all improve lipid levels and pro- vide other healthful benefits4,8,9 and should be undertaken regardless of whether pharmacotherapy is also recommended. Dietary and other changes in lifestyle recommended for the management of lipid levels are discussed further in the Supplementary Appendix.

LDL Cholesterol Level and Risk The direct relationship between LDL cholesterol level and the risk of atheroscle- rotic cardiovascular disease10 has led to the simple recommendation that “lower is better.” However, measurement of LDL cholesterol levels alone is not sufficient to assess cardiovascular risk. Approximately 40% of persons with coronary heart disease have a total cholesterol level of less than 200 mg per deciliter (5.2 mmol

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Exogenous Pathway Endogenous Pathway

Dietary

Free cholesterol Triglycerides Cholesterol Cholesteryl ester Phospholipids Phytosterols Fatty acids Squalene Degradation Stomach and Duodenum Mevalonate ApoB100 HMG CoA reductase Gastric and ABCA1 pancreatic ABCG5/G8 hydrolyze lipid acids HMG-CoA esters Phospholipids Cholesterol VLDL formation Acetyl-CoA Bempedoic Bile acids NPC1L1 acid PCSK9 LDLR Phospholipids Pyruvate Cholesterol PCSK9 inhibitor HDL Glucose formation Biliary micelle formation ApoER VLDL LDL Cholesteryl ester transfer protein Circulation Intestine Portal vein

Ezetimibe Bile acid sequestrants CD36 NPC1L1 IBAT

LDL ARTERIAL WALL ApoB 48 Bile acids LDL formed from VLDL formation remnants Foam cell VLDL PROXIMAL ILEAL ENTEROCYTE Atherogenesis Chylomicron and VLDL remnants LPL Chylomicron and VLDL Intestinal Hydrolysis LPL lymphatic lacteal Hydrolysis (to thoracic duct) Chylomicron Chylomicron remnants Chylomicron and VLDL remnants Circulation

Fatty acids Muscle internalized for use in (Energy use) muscles or converted into triglycerides for storage Apidose tissue (Energy storage)

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11 Figure 1 (facing page). Lipid Metabolism and Targets for Pharmacotherapy. per liter). Conversely, many persons with a The gastric lipid pool contains ingested free cholesterol, cholesterol esters, moderate elevation in LDL cholesterol level never phytosterols, triglycerides, phospholipids, and fatty acids (see exogenous have a clinical cardiovascular event. In the 2013 pathway). Gastric and pancreatic lipases hydrolyze lipid esters. Bile acids, ACC–AHA guidelines on the management of phospholipids, and cholesterol are secreted by hepatocytes by means of cholesterol,12 there was a movement away from specific transporters (ABCG5, ABCG8, and ABCB11) into the biliary system. targeting specific LDL cholesterol values and Conversely, the Niemann–Pick C1-like 1 (NPC1L1) protein facilitates the toward a focus on treatment of persons at the transfer of cholesterol from bile back into hepatocytes. Ezetimibe blocks biliary NPC1L1. Bile acids and lipids generate complex biliary micelles that greatest absolute risk of cardiovascular disease transport the lipids to intestinal microvilli absorption sites. NPC1L1 facili- with high-intensity statins.12 As cardiovascular tates the entry of cholesterol into , a step that is also blocked risk increases, so does the absolute benefit of by ezetimibe. Fatty-acid transport proteins such as CD36 regulate the ab- treatment with therapies proved to lower LDL sorption of de-esterified fatty acids and monoacylglycerols. Once freed cholesterol levels.13,14 Since publication of the from micelles, bile acids are reabsorbed by the ­ileal bile-acid transporter (IBAT) and released into the portal circulation for return to the liver. Bile-acid 2013 guidelines, additional findings from ran- 15,16 sequestrants block the reabsorption of bile acids in the . Cholesterol domized clinical trials have provided further and triglycerides are assembled into through a synthesis path- support for the concept that the magnitude of way that relies on microsomal transfer protein and apolipopro- event reduction is proportional to the degree to tein B48. Chylomicrons are secreted into the intestinal which LDL cholesterol is lowered.10,13 Thus, both ­before entering the circulation at the thoracic duct. Triglyceride-rich lipo- proteins, such as chylomicrons and very-low-density lipoproteins (VLDL), the absolute risk and the magnitude of the re- undergo lipolysis (hydrolysis of core triglycerides and surface phospholip- duction in LDL cholesterol level achieved are ids) through the interaction of apolipoprotein cholesterol-II and lipoprotein important. The 2018 cholesterol guidelines bring (LPL) in the muscle and adipocyte vascular beds, allowing fatty acids back recommendations for specific percentage to be internalized and used in muscles as an energy source or synthesized reductions in LDL cholesterol levels as well as into triglycerides for energy storage in adipocytes. The action of LPL on chylomicrons reduces their fatty-acid content and results in the production of the use of LDL cholesterol thresholds for the ad- chylomicron remnants; similarly, VLDLs are converted into VLDL remnants dition of nonstatin therapy to statins in patients (intermediate density lipoproteins [IDLs]). at high risk for atherosclerotic cardiovascular Hepatic synthesis of cholesterol (see endogenous pathway) begins with disease (Fig. 2).4 the conversion of glucose to pyruvate by means of a synthesis pathway that relies on the substrate acetyl coenzyme A (CoA), which is created during the Krebs cycle. β-hydroxy β-methylglutaryl-CoA (HMG-CoA) reductase is the Shared Decision Making rate-limiting enzyme in this pathway, forming squalene and several sterol intermediates and ultimately cholesterol. Statins inhibit HMG-CoA reduc- One critical feature of both the 2013 and 2018 tase. is a prodrug that is converted by the very-long-chain cholesterol guidelines is the recommendation acyl-CoA synthetase-1 (an enzyme present in hepatocytes but not myocytes) that clinicians conduct a general discussion of into an active metabolite that reduces the production of acetyl CoA in hepa- cardiovascular risk with patients before initiating tocytes by inhibiting ATP citrate lyase, thereby reducing cholesterol metab- 4,12 olism in the liver. By means of a synthesis pathway that relies on the action a . This shared decision-making process of microsomal triglyceride transfer protein, triglyceride joins with cholester- should involve a review of the patient’s major ol, cholesteryl ester, phospholipids, and -100 to assemble risk factors for cardiovascular disease and the into particles of VLDL cholesterol, which are secreted into the circulation. patient’s estimated level of risk within the next High-density lipoproteins (HDLs) are formed from the efflux of cholesterol 10 years. The adoption of a heart-healthy life- and phospholipids (by means of the membrane transporter ATP-binding cassette transporter A1 [ABCA1]) into apolipoprotein A-I (apoA-I) or smaller style should be encouraged and the evidence 17 HDL species. The efflux of cholesterol from arterial-wall foam cells to HDL base for lipid-lowering therapy discussed. The cholesterol is a crucial and specific part of HDL cholesterol function called conversation should also review the patient’s con- macrophage reverse cholesterol transport. Particles of low-density lipopro- cerns and preferences regarding initiation of pre- tein (LDL) cholesterol bind to and are cleared from plasma by LDL choles- ventive pharmacotherapy as well as the potential terol receptors. The liver synthesizes and secretes proprotein convertase for adverse effects from therapy.17 subtilisin–kexin type 9 (PCSK9), which binds to LDL cholesterol receptors, causing receptor catabolism when internalized by endosomes and lysosomes. PCSK9 inhibitors block this process. Atherogenesis occurs when apolipo- Lipid Management in Primary protein B–containing particles (including LDL cholesterol molecules, which Prevention are the most numerous, and chylomicron and VLDL remnants) enter the arterial wall, undergo oxidation, and are internalized by macrophages, creat- As a starting point to guide treatment decisions, ing foam cells. the 2018 and 2019 guidelines4,5 recommend use

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Promote a Healthy Lifestyle Figure 2. Five Key Points from the 2018 ACC–AHA Guidelines. A healthy lifestyle is appropriate for all patients as part of the management of cardiovascular risk, including adequate physical activity and a healthy diet. Decisions regarding cardiovascular risk management should be shared between clinician and patient, including inter- pretation of the patient’s 10-year risk of atherosclerotic cardiovascular disease. Recommendations for pharmaco- Share Decision Making with the Patient therapy are based on the patient’s individual risk pro- file and clinical characteristics. Statins remain the first- • Measure risk factors line agents, but for patients with clinical atherosclerotic cardiovascular disease at very high risk or for patients • Evaluate the patient’s risk of ASCVD with severely elevated LDL cholesterol levels, nonstatin agents, such as ezetimibe and PCSK9, may be consid- ered. Recommendations for statin therapy also include patients 40 to 75 years of age with a level of LDL choles- terol that is higher than 69 mg per deci­liter who have Determine Candidates for Pharmacotherapy diabetes or who have a 10-year risk of atherosclerotic cardiovascular disease equal to or greater than 7.5%. Ad- Statins remain first line ditional considerations should be made for younger or Clinical ASCVD older adults. After calculation of the ­patient’s 10-year • Reduce LDL cholesterol level by ≥50% risk of atherosclerotic cardiovascular disease, risk assess- with high-intensity statin (or maximum ment can be individualized by considering any risk-­ dose tolerated without side effects) enhancing factors and the patient’s coronary-artery • Consider nonstatin therapy in patients ­calcium score, if measured. The patient’s therapeutic at very high risk (LDL cholesterol response should continue to be monitored over time. threshold of ≥70 mg/dl while receiving maximum dose tolerated) Severely elevated LDL cholesterol (≥190 mg/dl) of the ACC–AHA Risk Calculator to estimate the • Prescribe high-intensity statin (up to highest tolerated dose) risk of atherosclerotic cardiovascular disease with- • Consider addition of nonstatin if needed (LDL in 10 years (www.​ cvriskcalculator­ .​ com/­ ).​­ 18 The cholesterol remains ≥100 mg/dl in patient calculator is intended for adults 40 to 75 years with risk factors) of age who do not have diabetes and whose LDL Diabetes cholesterol level is 70 mg per deciliter (1.8 mmol • Prescribe moderate-intensity statin per liter) or higher but lower than 190 mg per • Consider reducing LDL cholesterol level by ≥50% in patients at high risk deciliter (4.9 mmol per liter). After risk estima- 10-yr risk of ASCVD ≥7.5% tion, patients can be categorized according to • Prescribe moderate-intensity statin if discussion favors therapy after their risk of disease at 10 years: low (<5%), border- consideration of risk-enhancing factors, coronary artery calcium, or both line (5 to <7.5%), intermediate (≥7.5 to <20%), or • Reduce LDL cholesterol level by ≥30% (or ≥50% if 10-yr risk ≥20%) high (≥20%).4,5 For most patients at low risk for disease, reinforcement of lifestyle changes alone Adopt a Personalized Approach is often sufficient. For those at high risk, the use of a high-intensity statin to reduce the LDL cho- • Consider additional factors that increase risk lesterol level by 50% or more is recommended in • If level of risk is uncertain, consider coronary- combination with adoption of a healthy lifestyle.4,5 artery calcium test For those at intermediate risk, the initiation of a moderate-intensity statin to reduce the LDL cho- Monitor Response to Treatment and Lifestyle lesterol level by 30% or more is recommended along with adoption of a healthy lifestyle.4,5 The presence of risk-enhancing factors favors the initiation or intensification of statin therapy in patients at intermediate risk and justifies the initiation of therapy among adults with border- line risk.4,5 These risk-enhancing factors include a history of preeclampsia, early menopause, rheu-

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matologic disease, human immunodeficiency Primary Prevention in Severe virus infection, a strong family history of prema- Hypercholesterolemia ture coronary heart disease, South Asian ances- or Diabetes try, chronic kidney disease, persistently elevated triglyceride levels, a low ankle–brachial index, For persons with severe primary hypercholester- and elevated levels of high-sensitivity C-reactive olemia (an LDL cholesterol level ≥190 mg per protein, lipoprotein(a), or apolipoprotein B.4,5 deciliter), the likelihood of a familial hypercho- The 2018 and 2019 ACC–AHA guidelines rec- lesterolemia is increased and there is no need to ognize that the benefits of lipid pharmacother­ calculate the 10-year risk of atherosclerotic car- apy remain uncertain in persons whose risk of diovascular disease; treatment is recommended atherosclerotic cardiovascular disease at 10 years to mitigate the substantial lifetime risk of dis- is 5 to <20%.4,5 Among patients at intermediate ease. A high-intensity statin (or the maximum risk and selected patients with borderline risk tolerated dose) is recommended.4,5 If the LDL for disease, it may be reasonable to measure the cholesterol level remains 100 mg per deciliter or burden by assessing the coronary- higher (≥2.6 mmol per liter), it is reasonable to artery calcium score with computed tomography consider treatment with ezetimibe, a proprotein (without administration of contrast material) to convertase subtilisin–kexin type 9 (PCSK9) in- further refine risk estimation either upward or hibitor, or both. downward.4,5,19,20 Statins are generally recommend- In patients with diabetes who are between 40 ed for persons who have a coronary-artery cal- and 75 years of age and have an LDL cholesterol cium score that is 100 or higher or who are in level of 70 mg per deciliter or higher, there is the 75th percentile or higher for their age, sex, also no need to calculate 10-year risk. A moder- and race. Statins should also be considered in ate-intensity statin should be recommended.4,5 persons with scores of 1 to 99, particularly if For patients with diabetes who are at a higher they are 55 years of age or older.4,5 On the other risk for atherosclerotic cardiovascular disease hand, a coronary-artery calcium score of 0 identi- owing to multiple risk factors, it is reasonable to fies persons among whom event rates are expect- prescribe a high-intensity statin to reduce the ed to be well below 7.5% over a 10-year period.21-24 LDL cholesterol level by 50% or more. For such persons, treatment with statins may be withheld or deferred (with the exception of ciga- Lipid Management in Secondary rette smokers25 and persons with familial hyper- Prevention cholesterolemia26). Estimation of lifetime cardiovascular risk may For patients 75 years of age or younger who have be considered in adults younger than 40 years of clinical atherosclerotic cardiovascular disease, age or those 40 to 59 years of age who have a the LDL cholesterol level should be reduced by at 10-year risk of disease that is less than 7.5% to least 50% with the use of a high-intensity statin facilitate the discussion of risk between clinician (or the maximum tolerated dose).4 If the LDL and patient and to emphasize the value of efforts cholesterol level remains at 70 mg per deciliter to maintain a healthy lifestyle.5 The use of statins or higher with the maximum tolerated dose of for primary prevention in the treatment of patients statin therapy, it may be reasonable to add older than 75 years of age should be considered ezetimibe. Among patients at very high risk — in the context of a shared decision-making pro- such as those who have had recent onset of an cess that factors in the patient’s coexisting condi- acute coronary syndrome, multiple events related tions, life expectancy, and preferences. to atherosclerotic cardiovascular disease, or a prior In summary, with consideration of risk-enhanc- cardiovascular event with multiple risk factors ing factors and coronary-artery calcium score (if and those with an LDL cholesterol level ≥70 mg assessed) in the context of a discussion of risk per deciliter despite receiving the maximum tol- between clinician and patient, the 2018 and 2019 erated dose of statins — the addition of ezeti- ACC–AHA guidelines allow for personalized treat- mibe is reasonable. If the LDL cholesterol level ment decisions regarding lipid management in is still 70 mg per deciliter or higher, a PCSK9 the primary prevention of atherosclerotic cardio- inhibitor can be added.4 vascular disease.4,5 For patients 75 years of age or older, initiation

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or continuation of a moderate- or high-intensity actually caused by anticipation of negative ef- statin is reasonable. The statin dose may need to fects.31 An ongoing study, SAMSON (Self-Assess- be reduced in patients at risk for adverse effects ment Method for Statin Side Effects or Nocebo; from polypharmacy and altered pharmacokinetics. ClinicalTrials.gov number, NCT02668016), may offer more insights. Overview of Lipid-Lowering Once initiated, statins should generally be Drugs continued long-term. The benefits are greater in the second, third, and fourth years than in the Statins first year. In long-term follow-up of the West Statins remain the primary pharmacotherapy of Scotland Coronary Prevention Study, 5 years of used to lower LDL cholesterol levels. Statins are statin treatment were reported to confer a 20-year competitive inhibitors of 3-hydroxy-3-methylglu- legacy of continued benefit.32 taryl coenzyme A (HMG-CoA) reductase, which affects the rate-controlling step in cholesterol Ezetimibe synthesis27 (Fig. 1). Inhibition of HMG-CoA reduc- Ezetimibe blocks the Niemann–Pick C1-like 1 cho- tase leads to increased expression of the hepatic lesterol transfer protein to inhibit intestinal and LDL receptor and increased clearance of LDL biliary cholesterol absorption, leading to an in- from the circulation. crease in the expression of hepatic LDL recep- Meta-analyses of randomized, controlled trials tors27 (Fig. 1). In IMPROVE-IT (Improved Reduc- have reported that for every reduction of 39 mg tion of Outcomes: Vytorin Efficacy International per deciliter (1.0 mmol per liter) in LDL choles- Trial), among patients with acute coronary syn- terol level, statins confer relative reductions in drome whose LDL cholesterol levels were less cardiovascular events and all-cause mortality of than 125 mg per deciliter (3.2 mmol per liter), 22% and 10%, respectively.2,28 More intensive the addition of ezetimibe to con- statin regimens conferred a reduction in major ferred a significant reduction in the absolute risk adverse cardiovascular events that was 15% great- of recurrent cardiovascular events of 2 percent- er than that conferred with less intensive regi- age points (constituting a 6% reduction in rela- mens.2 Trials focused exclusively on primary pre- tive risk).15 This finding translates to a number vention reported similar and significant relative needed to treat of 50 to prevent 1 major cardio- reductions in fatal or nonfatal atherosclerotic vascular event over 7 years. The median LDL cardiovascular disease events.3 cholesterol level achieved was 54 mg per deciliter For the vast majority of patients in whom (1.4 mmol per liter) in the group receiving sim- statins are indicated, the benefits outweigh the vastatin and ezetimibe as compared with 70 mg risks.29 The risk of serious muscle injury, includ- per deciliter with simvastatin alone, providing ing rhabdomyolysis, associated with statins is evidence of additional benefit with further lower- very low (<0.1%) and the risk of serious liver ing of LDL cholesterol level.33 Ezetimibe is used injury is even lower (approximately 0.001%). in patients who have unacceptable side effects There is a modest increase in the risk of diabetes with statins, who have severe primary hypercho- mellitus of 0.2% per year (depending on the lesterolemia, or who have insufficient reduction person’s baseline risk for diabetes), but the bene­ in LDL cholesterol levels when taking the maxi- fits of statins generally also outweigh risks for mum tolerated statin dose. Because no outcomes patients with diabetes. trial has shown benefit with ezetimibe when There is controversy regarding the extent used in isolation, those who take ezetimibe be- of myalgia that is related to statins. The rate of cause of statin intolerance should continue to myalgia is low in blinded randomized trials,29 take the maximum tolerated statin dose. although these trials generally have a run-in phase to screen for side effects. Higher rates of myalgia PCSK9 Inhibitors are reported more frequently in clinical prac- Gain-of-function mutations in PCSK9 are a cause tice,30,31 but it remains uncertain how frequently of familial hypercholesterolemia,34 and loss-of- the symptoms reported are truly attributable to function mutations are associated with a pheno- statins or to “nocebo” effects, in which patients type of lower LDL cholesterol levels and a lower may perceive side effects of that are risk of coronary heart disease than are found in

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persons who do not have loss-of-function muta- tion, stroke, death from cardiovascular causes, tions.35 The PCSK9 enzyme binds to the LDL re- or hospitalization for angina. The trial included ceptor to promote its internal hepatic degradation. a dose-adjustment strategy to reach an LDL cho- PCSK9 inhibitors are subcutaneously injected lesterol level of 25 to 50 mg per deciliter (0.6 to monoclonal antibodies that inactivate the PCSK9 1.3 mmol per liter). Over a median of 2.8 years, enzyme, which in turn increases the availability the mean LDL cholesterol level in patients receiv- of LDL receptors on hepatocytes, thereby pro- ing was 38 mg per deciliter (1.0 mmol moting the removal of LDL cholesterol from the per liter). They also had a significant absolute circulation (Fig. 1). The result is a dramatic re- reduction in risk of 1.6 percentage points, repre- duction in LDL cholesterol levels of approximately senting a relative reduction of 15%, for the pri- 60%.16,36 The PCSK9 inhibitor also mary outcome of myocardial infarction, stroke, lowers mean lipoprotein(a) levels by 27%.37 death from cardiovascular causes, or hospital- The FOURIER (Further Cardiovascular Out- ization for angina. There was also an absolute comes Research with PCSK9 Inhibition in Sub- reduction in risk of 0.6 percentage points in jects with Elevated Risk) trial16 enrolled more all-cause mortality, representing a 15% reduction than 27,000 persons with stable atherosclerotic in relative risk. The reduction in all-cause mor- cardiovascular disease and an LDL cholesterol tality did not reach the prespecified definition level of 70 mg per deciliter or higher or a non-HDL for statistical significance.36 cholesterol level of 100 mg per deciliter (2.6 mmol PCKS9 inhibitors are used for high-risk pa- per liter) or higher despite receipt of moderate- or tients (for secondary prevention or severe primary high-intensity statin therapy. Participants were hypercholesterolemia) who have adverse reactions randomly assigned to receive evolocumab or to statins or who have an insufficient reduction placebo. The primary outcome was death from in LDL cholesterol level while taking the maxi- cardiovascular causes, myocardial infarction, mum tolerated dose of a statin plus ezetimibe. stroke, hospitalization for unstable angina, or There appears to be a linear relationship between coronary revascularization. Over a median of reduced LDL cholesterol level and lower cardio- 2.2 years, the median LDL cholesterol level de- vascular risk, even down to LDL cholesterol val- clined to 30 mg per deciliter (0.8 mmol per liter) ues of less than 10 mg per deciliter (0.3 mmol in persons receiving evolocumab. They also had per liter), with no early signal for harm associ- a rate of major adverse cardiovascular events that ated with very low LDL cholesterol levels.40 Safety was 1.5 percentage points lower than the rate beyond 3 years is not yet well established, and among those who were not taking evolocumab, PCSK9 inhibitors may not be reasonably cost- corresponding to a relative reduction in events of effective for the average patient until the annual 15%.16 The absolute reductions in risk conferred cost falls below $5,500.41 Burdensome preauthori- by evolocumab were greater among those who zation procedures have been a barrier to access had a higher absolute risk of these events, such to this therapy for many patients.42 as persons with peripheral artery disease,38 a history of recent or multiple myocardial infarc- n–3 Fatty Acids tions,39 or elevated lipoprotein(a) levels.37 How- Long-chain n–3 polyunsaturated fatty acids, which ever, no significant reduction in mortality was can be a mixture of eicosapentaenoic acid (EPA) seen over this short-term follow-up period. and docosahexaenoic acid or EPA alone, reduce The ODYSSEY OUTCOMES trial tested the triglyceride levels by reducing production of very- benefit of alirocumab in patients who had had low-density lipoprotein (VLDL) cholesterol in the an acute coronary syndrome within the past year liver and to a lesser extent by increasing VLDL and who had an LDL cholesterol level of at least cholesterol clearance from the circulation. Patients 70 mg per deciliter, a non-HDL cholesterol level with severe hypertriglyceridemia (triglyceride of at least 100 mg per deciliter, or an apolipopro- level >500 mg per deciliter [5.6 mmol per liter]) tein B level of at least 80 mg per deciliter despite typically need to be treated with 4 g per day of taking the maximum tolerated dose of a statin.36 n–3 fatty acids to reduce triglyceride levels by Nearly 19,000 patients were randomly assigned to 20 to 30%.43 receive alirocumab or placebo and were followed Early open-label trials, including GISSI (Gruppo for the primary outcome of myocardial infarc- Italiano per lo Studio della Sopravvivenza

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nell’Infarto Miocar dico)–Prevenzione44 and JELIS reduce the rate of major cardiovascular events in (Japan Eicosapentaenoic Acid Lipid Intervention patients with hypertriglyceridemia and low HDL Study)45 suggested benefit from n–3 fatty acids cholesterol levels, despite controlled LDL choles- for reduction of the risk of coronary heart dis- terol levels. ease. However, two recent meta-analyses, which included randomized, controlled trials published Other Agents through 2017, reported no significant reduction The development of the medications discussed in vascular events with n–3 therapy.46,47 Neither above has led to a decline in the use of older the VITAL (Vitamin D and Omega-3) trial48 nor agents, such as , , and bile-acid ASCEND (A Study of Cardiovascular Events in sequestrants, which were previously mainstays Diabetes),49 published in 2019 and 2018, respec- of lipid management. These agents, as well as tively, reported a benefit from the use of n–3 restricted-use therapeutics reserved for the treat- therapy at a dose of 1 g per day with respect to ment of severe lipid disorders, are discussed in the primary composite outcome of major adverse the Supplementary Appendix. cardiovascular events. In contrast, in REDUCE-IT (Reduction of Car- Emerging Approaches diovascular Events with Icosapent Ethyl–Inter- Inclisiran is a small interfering RNA designed to vention Trial), the risk of major adverse cardio- target PCSK9 messenger RNA and thus inhibit vascular events was significantly lower, by 25%, PCSK9 synthesis.51 It has the potential benefit of among patients who received 4 g of icosapent far lower dose frequency than treatment with ethyl daily than among those who received pla- monoclonal antibodies to PCSK9. A phase 2 ran- cebo.50 REDUCE-IT enrolled patients with high domized trial in which inclisiran was compared baseline risk (known atherosclerotic cardiovas- with placebo showed dose-dependent reductions cular disease or diabetes mellitus plus at least in PCSK9 and LDL cholesterol levels.52 ORION-4 one additional vascular risk factor) who had LDL (A Randomized Trial Assessing the Effects of cholesterol levels that were controlled with statin Inclisiran on Clinical Outcomes among People therapy but who had elevated triglyceride levels with Cardiovascular Disease; NCT03705234) is (135 to 500 mg per deciliter [1.5 to 5.6 mmol per a large, ongoing, phase 3 trial investigating liter]). Icosapent ethyl is a proprietary and high- whether inclisiran can reduce major cardiovas- ly purified form of EPA, and the findings from cular events in adults with established cardio- REDUCE-IT should not be generalized to apply vascular disease. to recommendations regarding dietary supple- Bempedoic acid is an inhibitor of ATP citrate mentation with fish oil. lyase that up-regulates LDL receptors by reduc- Because the reduction in cardiovascular risk ing cholesterol synthesis.51 The active metabolite seen with icosapent ethyl exceeded the anticipated requires an enzyme not thought to be present in benefits from the observed reduction in triglycer- myocytes, so the absence of side effects that af- ide levels (approximately 20%), other potentially fect muscle is a potential benefit of this drug as beneficial mechanisms, such as antiinflamma- compared with statins. In the CLEAR Harmony tory or antithrombotic effects, have been enter- (Evaluation of Long-Term Safety and Tolerability tained. The use of icosapent ethyl for the preven- of ETC-1002 in High-Risk Patients with Hyper- tion of cardiovascular events was not discussed lipidemia and High Cardiovascular Risk) trial, in the guidelines on cholesterol management patients who received maximally tolerated statin published by the ACC–AHA in 2018,4 but this therapy administered with bempedoic acid had therapy may play a key role in future recommen- significantly lower LDL cholesterol levels than dations for the prevention of cardiovascular dis- those who received placebo (mean difference, ease once confirmatory studies have been pub- 18%), without an increase in serious adverse lished. In the ongoing STRENGTH (Outcomes events.53 The efficacy and safety of bempedoic Study to Assess Statin Residual Risk Reduction acid will be further determined in a larger car- with EpaNova in High Cardiovascular Risk Patients diovascular outcome trial, CLEAR-OUTCOMES with Hypertriglyceridemia) trial (NCT02104817), (Evaluation of Major Cardiovascular Events in researchers are evaluating whether n–3 carbox- Patients with, or at High Risk for, Cardiovascu- ylic acids, prescribed at a dose of 4 g per day, can lar Disease Who Are Statin Intolerant Treated

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with Bempedoic Acid [ETC-1002] or Placebo; rated LDL cholesterol thresholds for the addition NCT02993406), which is enrolling 12,600 patients of nonstatin therapy to statin therapy4; however, at high cardiovascular risk who have adverse it is noteworthy that the Friedewald equation, effects in response to statins and have an LDL which is used to estimate LDL cholesterol levels, cholesterol level of 100 mg per deciliter or higher. can be inaccurate when LDL cholesterol levels 57 AKCEA-APO(a)-LRx is an antisense oligonucleo­ are very low or when triglyceride levels are ele- tide drug targeting lipoprotein(a) that can reduce vated. The Martin–Hopkins LDL cholesterol esti- lipoprotein(a) levels by up to 90% and appeared mation is an “adaptable” method that is used to to be safe in phase 2 trials (e.g., Phase 2 Study gauge the LDL cholesterol level by applying an of ISIS 681257 [AKCEA-APO(a)-LRx] in Patients adjustable factor for the ratio of triglycerides to with Hyperlipoproteinemia[a] and Cardiovascu- VLDL cholesterol (www.​ hopkinsmedicine­ .​ org/­ apps/​­ ​ lar Disease; NCT03070782).51 It is planned to be all­ -​ apps/­ ldl​­ -​ cholesterol­ -​ calculator).­ It is more ac- evaluated next in a phase 3 cardiovascular out- curate than the Friedewald method, particularly comes trial. Also under study are drugs target- for those with elevated triglyceride levels58 or low ing angiopoietin-like 3 (ANGPTL3), either with LDL cholesterol levels; it also performs better on monoclonal antibodies or antisense oligonucle- nonfasting samples.59 otides, which have shown promise in early-phase Although this review focuses on the guide- trials.51,54 ANGPTL3 is an inhibitor of lipoprotein lines put forth by the ACC–AHA, it is important lipase; thus inhibition of ANGPTL3 lowers levels to note that other guidelines have been published of triglycerides and LDL cholesterol.51 A phase 2 separately by the U.S. Preventive Services Task study of an antisense drug that targets apolipo- Force,60 the Department of Veterans Affairs,61 protein C3 (NCT03385239), involving patients with the National Lipid Association,62 the American hypertriglyceridemia, has also been completed. Association of Clinical Endocrinologists,63 and the European Society of Cardiology–European 64 Additional Considerations Atherosclerosis Society (reviewed in Table S2). These guidelines also endorse statins for use in The 2018 cholesterol guidelines recommend mea- secondary and primary prevention for patients at surement of lipid levels every 4 to 12 weeks after high risk for cardiovascular events (with the deci- the initiation of a statin or dose adjustment to sion to initiate or adjust pharmacotherapy made assess patient adherence to the prescription and on the basis of absolute risk of cardiovascular the extent of reduction in the LDL cholesterol disease), but there are differences between these level.4 Subsequently, periodic measurement of guidelines and the 2018 ACC–AHA guidelines, lipids (every 3 to 12 months) is reasonable. For such as the 10-year-risk estimation cutoff points most patients, fasting is not required before used to classify levels of elevated risk, the inten- testing, although a fasting lipid profile may be sity of the statin recommended, and the LDL still be beneficial in the evaluation of genetic hy- cholesterol thresholds for treatment. perlipidemia, premature atherosclerotic cardiovas- cular disease, or persistent hypertriglyceridemia. Conclusions Statin intolerance is defined as the inability to receive at least two different statins, including Management of serum cholesterol is a central one administered at the lowest starting daily dose. objective in the effort to prevent atherosclerotic Several publications have provided more detailed cardiovascular events. A discussion of cardiovas- guidance on how to approach the treatment of cular risk is warranted in all patients. Lifestyle patients with statin intolerance,55,56 which typi- changes targeted at improving a patient’s lipid cally includes a review of drug–drug interactions profile form the foundation for prevention, along and of other health conditions that can cause with management of other cardiovascular risk muscle-related symptoms and discontinuation of factors.5,65,66 For patients whose risk of cardio- the statin, with subsequent rechallenge (ideally vascular disease is sufficiently elevated to sug- with the use of a statin with pharmacokinetics gest a net benefit, pharmacologic treatment with that are different from those of the initial statin) statins is recommended, with the intensity of to verify muscle-related symptoms. treatment matching the absolute baseline level The 2018 cholesterol guidelines have incorpo- of cardiovascular risk. For patients at high risk

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who have not had the anticipated reduction in glyceride levels. New therapies for lowering lipid LDL cholesterol level of 50% or more or who have levels are showing promising results in early clini- a residual LDL cholesterol level of 70 mg per deci- cal trials and are awaiting confirmation of benefit liter or higher despite therapy with the maximum and safety in large cardiovascular outcome stud- tolerated dose of a statin, ezetimibe, with or ies. The results of these studies may change the without a PCSK9 inhibitor, may be considered ways in which lipids are managed in the future. for secondary prevention. High-dose EPA has Disclosure forms provided by the authors are available with emerged as a promising therapy for additional the full text of this article at NEJM.org. We thank Thomas Dayspring, M.D., chief academic officer of cardiovascular event reduction among patients True Health Diagnostics, for his assistance with an earlier ver- taking statins who have residual elevation in tri- sion of Figure 1.

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